The long-term overall goal of the Recanalization Therapies and Markers of Stroke Outcome - Specialized program of Translational Research in Acute Stroke (SPOTRIAS) is to enhance and accelerate recovery of acute stroke patients by focused and innovative rapid interventions for ischemic and hemorrhagic stroke. Stroke is a significant problem in the U.S., and causes much mortality and morbidity. This disease will increase in prevalence as the population ages. Currently, the only FDA approved therapy for acute ischemic stroke is the administration of recombinant tissue plasminogen activator (rt-PA). However, rt-PA must be administered within 3 hours of onset, and can have side effects such as intra-cerebral hemorrhage (ICH). This has led to interest in other therapies such as hypothermia, other lytic medications, and ultrasound (US) enhanced thrombolysis (UET). Ultrasound has been known to enhance rt-PA lytic efficacy for some time, this has motivated several clinical trials of UET in stroke. However, the "best" UET stroke treatment is not known. AV Alexandrov showed that stroke patients treated with 2 MHz transcranial Doppler and rt-PA exhibited better vessel recanalization and a trend towards improved neurologic outcome compared with rt-PA alone. However, a similar study comparing 300 kHz UET and standard rt-PA treatment did not show improved outcome. Also, 300 kHz UET treated patients exhibited a greater ICH rate. Clearly, safety is an issue in utilizing UET therapy for ischemic stroke. In TRUST (Transcranial Ultrasound Treatment for Stroke), we will determine the optimal UET parameters for acute ischemic stroke. Efficacy will be determined by measuring the lytic rate and total clot lysis of combined US and rt-PA in an in-vitro human clot model. The physical dimensions of the sample clot are measured over time during lytic treatment. Optimal parameters are those that maximize clot lysis. Minimization of bioeffects of these parameters will be verified by measuring the acoustic field within cadaveric human skulls. Demonstration of optimal UET therapy will improve treatment of acute ischemic stroke. The results of this work will yield UET treatment parameters for optimized in-vivo and clinical trials of this therapy. Improved stroke treatment would reduce mortality and morbidity and improve the overall public health. PUBLIC HEALTH RELEVANCE: Completion of the SPOTRIAS program will substantially improve the public health by improving stroke treatment. The projects contained within this grant will result in the creation of new therapies and treatments for stroke. These results can then be readily transferred from "bench to bedside" within the SPOTRIAS network, thus improving clinical stroke care.